Zibin Feng, Lin Wu, Ying Shen, Yuqi Hu, Zhiguo Zhang
Solute carrier family 39 member 8 (SLC39A8) exhibits abnormal expression in a broad range of tumors and is closely associated with the progression of malignant tumors. However, its expression patterns and functional roles in glioma remain unexplored. This research aimed to investigate the key regulatory function of SLC39A8 in the malignant phenotypes of glioma and its possible value as a therapeutic candidate for this malignancy. Bioinformatics analysis and experimental validation revealed elevated SLC39A8 levels in gliomas, with strong associations with clinicopathological traits and patient prognostic status. The results of functional assays revealed that SLC39A8 knockdown elicits robust anti-glioma effects. Notably, re-expression of SLC39A8 in SLC39A8-depleted glioma cells markedly reversed these anti-tumor effects. Further investigation demonstrated that SLC39A8 knockdown enhances lipid peroxidation and induces ferroptosis and that treatment with ferroptosis inhibitors significantly counteracts the tumor-suppressive impact of SLC39A8 knockdown. Mechanistically, SLC39A8 mediates zinc influx, which activates cyclic adenosine monophosphate-responsive element-binding protein (CREB)-mediated glutathione peroxidase 4 (GPX4) transcription, thereby modulating ferroptosis. Overexpression of GPX4 strongly reversed the ferroptosis induction resulting from SLC39A8 knockdown. In vivo glioma xenograft models further confirmed that SLC39A8 knockdown suppressed tumor formation and increased ferroptosis in tumor tissues. Collectively, our findings indicate that SLC39A8 plays a protumorigenic role in glioma and that its knockdown suppresses tumor progression, likely by modulating CREB/GPX4-mediated ferroptosis. This study offers new perspectives on the molecular pathogenic mechanisms of glioma and highlights SLC39A8 as a potential promising target for treating this malignant tumor.